A physiological and translational liver model to study the metabolism-modulating roles of extracellular matrix microstructures

用于研究细胞外基质微结构的代谢调节作用的生理和转化肝脏模型

• 批准号: 10676333
• 负责人: Chengpeng Chen
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676333
• 关键词: 3-Dimensional; 5' -AMP-activated protein kinase; Architecture; Cellular Metabolic Process; Dedications; Development; Extracellular Matrix; Fibrosis; Future; Hepatic; Homeostasis; Impairment; Integrins; Laboratories; Literature; Liver; Logic; Maintenance; Metabolic; Microfluidics; Modeling; Pharmacologic Substance; Physiological; Property; Proteins; Reporting; Research; Risk; Role; Structure; Technology; Testing; Time; Tissue Model; Work; cell type; cost; drug development; fabrication; human subject; innovative technologies; insight; liver metabolism; metabolic abnormality assessment; novel therapeutics; operation; screening; success; therapy development

ABSTRACT My laboratory has been dedicated to developing physiologically relevant yet easy-to-apply tissue modeling technologies, and exploring the interactions between extracellular matrix (ECM) microstructures and cell metabolisms. Building on recent successes and discoveries, we propose to develop a more advanced technology for liver modeling, and to profoundly study how fibrosis-relevant ECM microstructures can impair hepatic metabolism—the former aims to reduce the monetary/time costs and human subject risks in new drug development, and the latter will provide new understanding and metabolic targets for fibrosis treatments. Although various microfluidic liver models have been reported, they lack the critical compositions of the physiological liver, namely, all the necessary cell types, the relevant architecture, and physiological 3D ECMs. Both literature and our preliminary results suggest the crucial roles of these components in maintaining hepatic functions and homeostasis, which may explain why current liver models could only mimic part of the functions. Integrating the various cell types, the cellular architecture, and the 3D ECMs represents challenging hurdles by the available technologies. Therefore, we propose an innovative technology to model the liver with a new fabrication logic, workflow, and set of technical means. This technology will recapitulate the most liver niche properties heretofore, but with relatively simple and straightforward operations (setting up, maintenance, analyses, etc.). We recently reported for the first time that ECM microstructures could modulate metabolic activities in various cell types. Based on this, we propose to set up ECM controls that mimic healthy and fibrotic conditions, and thoroughly investigate how the aberrantly remodeled ECMs can impair hepatic metabolisms. Mechanistic studies involving integrins and AMP-activated protein kinase are also planned. To summarize, there has not been a tissue modeling technology like the proposed one; and others have not reported the interactions between ECM microstructures and cell metabolism. The proposed work, therefore, represents high novelty and my laboratory’s unique space in the field. Completing the proposed studies will be significant for pharmaceutical developments because a new testing/screening platform and metabolic (metabolites and the controlling proteins) targets will be provided for future fibrosis therapies.

摘要